One of the functions served by the epidermis in mammals is to form a barrier against excessive transcutaneous water loss to the environment. This barrier is formed by the anucleate, cornified, outermost layers of the epidermis, collectively known as the stratum corneum. Localized or generalized perturbations of the epidermal barrier occur in a variety of diseases and conditions of the skin and mucous membrane. These perturbations not only contribute significantly to the morphology of cutaneous lesions, but also activate certain skin diseases such as the Koebner phenomenon in psoriasis and the inflammation in eczematous disorders. The integrity of the barrier is also known to be a major factor in regulating epidermal DNA synthesis. Thus, maintenance of a normal epidermal barrier is a physiological means of inhibiting epidermal hyperproliferation. Examples of conditions that involve or give rise to a disrupted or dysfunctional epidermal barrier are:
fluid and electrolyte abnormalities, hypothermia, and infection through the skin in premature infants less than 33 weeks of gestational age;
inflammation to mucous membranes, such as cheilitis, chapped lips, nasal irritation and vulvovaginitis;
eczematous dermatitides, such as atopic and seborrheic dermatitis, allergic or irritant contact dermatitis, eczema craqueldxc3xa9e, photoallergic dermatitis, phototoxic dermatitis, phytophotodermatitis, radiation dermatitis, and stasis dermatitis;
ulcers and erosions resulting from trauma, burns, bullous disorders, or ischemia of the skin or mucous membranes;
several forms of ichthyoses;
epidermolysis bullosae;
psoriasis;
hypertrophic scars and keloids;
cutaneous changes of intrinsic aging and photoaging;
frictional blistering caused by mechanical shearing of the skin; and
cutaneous atrophy resulting from the topical use of corticosteroids.
The key constituents of the epidermis that are needed for a functional barrier are the intercellular, lamellar bilayer sheets of stratum corneum lipids. The synthesis of stratum corneum lipids is relatively autonomous from circulating or dietary influences. The synthetic response is regulated instead by alterations in permeability barrier functions. The regulation occurs through changes in the activities, phosphorylation (activation) state, mass, and mRNA for the rate-limiting enzymes of each of the three key lipids: serine palmitoyl transferase (for ceramides), HMGCoA reductase (for cholesterol), and both acetyl CoA carboxylase and fatty acid synthase (for fatty acids). Other results of alterations in barrier function are the regulation of key enzymes of extracellular lipid processing. One such enzyme is xcex2-glucocerebrosidase, which catalyzes the conversion of precursor glycosylceramides into ceramides.
While permeability barrier requirements regulate lipid synthesis, the endogenous regulators of barrier development and homeostasis are not known. Recent studies from the inventors"" laboratories have shown that several activators and ligands of the nuclear receptor superfamily, such as glucocorticoids, thyroid hormone, and estrogen, accelerate the appearance of a mature barrier in fetal rodent skin. Hanley, K., et al., xe2x80x9cEpidermal barrier ontogenesis: maturation in serum-free media and acceleration by glucocorticoids and thyroid hormone but not selected growth factors,xe2x80x9d J. Invest. Dermatol. 106:404-411 (1996); Hanley, K., et al., xe2x80x9cHormonal basis for the gender difference in epidermal barrier formation in the fetal rat. Acceleration by estrogen and delay by androgen,xe2x80x9d J. Invest. Denmatol. 97:2576-2584 (1996). In contrast, other members of this family, such as 1,25-dihydroxy vitamin D3 9-cis-retinoic acid, and all-transretinoic acid, had no effect.
It has now been discovered that the formation of a mature, fully differentiated stratum corneum and a functional epidermal permeability barrier are accelerated by the topical administration of certain activators of any one of three nuclear receptors-the farnesoid X-activated receptor (FXR), the peroxisome proliferator-activated receptor xcex1 (PPARxcex1), and the liver-based receptor known as LXRxcex1. These three receptors are nuclear receptors and are part of the nuclear receptor superfamily of transcription factors. The three receptors reside in a subgroup of the superfamily, all receptors in the subgroup sharing the feature that they function only when having formed heterodimers with the retinoid X receptor (RXR). Many other members of the subgroup however do not have activators that accelerate the formation of a mature stratum corneum or barrier developmentxe2x80x94these include the vitamin D receptor (VDR), the all-trans-retinoic acid receptors (RARxcex1,xcex2,xcex4), and the 9-cis-retinoic acid (RXR) receptor. The ability of FXR, PPARxcex1 and LXRxcex1 activators to achieve this result is therefore unique among members of this subgroup.
The ability of FXR activators to accelerate barrier development is particularly surprising since compounds similar in structure to farnesol (a prominent FXR activator) that are not themselves FXR activators do not accelerate barrier development, despite the similarity in structure to those that do. Also surprising is the ability of the PPARxcex1 receptor, since other PPAR receptors exist (with their own separate activators) that are similar in structure and function, and yet only activators of the PPARxcex1 receptor accelerate barrier development. A further surprising aspect of this discovery is that the barrier development acceleration associated with PPARxcex1 activation is nm related to any distinction between essential and non-essential fatty acids, but rather to certain common structural features. A still further surprising aspect of the discovery relates to oxysterols that are not activators of LXRxcex1 but are very close in structure to those that are. The oxysterols that are not LXRxcex1 activators do not produce the beneficial results of this invention despite their similarity in structure. Furthermore, many of the activators that are the subject of this invention have never before been known to have any utility as topical epidermal agents.
This newly discovered activity of the three classes of activators renders them useful in the treatment of mammalian skin suffering deficient or perturbed barrier function. The invention is particularly useful in the treatment of premature infants, particularly those less than 33 weeks of gestational age. This invention is also useful for alterations in epidermal differentiation and proliferation. Applications include melanoma and non-melanoma skin cancers and skin precancers, disorders of epidermal differentiation and proliferation such as psoriasis, atopic dermatitis, and various types of ichthyosis with or without an associated barrier abnormality; and benign neoplasms such as warts, condylomata, and seborrheic keratoses.
Other features and advantages of the invention will become apparent from the description that follows.